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Jennifer Honek From bench to bedside – the cohorts. 1 In Phase I studies, the IND is Honek Communications Consulting & Medical long journey from the lab into administered to humans for the first time. 3 Early Writing, Stockholm, Sweden the clinic Phase I studies (previously Phase 0) describe Developing a novel drug is an interdisciplinary first-in-human studies where a small group of endeavour involving a multitude of competences subjects, usually 10 to 15 individuals, received a Correspondence to: from biologists, chemists, computer scientists, single, sub-therapeutic dose to obtain pharma - Honek Communications Consulting medical staff, statisticians, and regulatory experts. cokinetic information without inducing pharma - & Medical Writing Taking a compound from bench to bedside cological effects. The goal of these exploratory Stockholm, Sweden requires up to 12 years at an average estimated studies is to investigate whether the drug [email protected] cost exceeding US $1 billion. 1 Figure 1 sum - candidate performs as expected based on marises this long-term process (see overleaf). preclinical studies. If successful, further studies Drug development starts with the iden ti - assess safety and tolerance of the IND in human Abstract fication of a “druggable” target. Bio informatics, subjects. These studies typically involve 20–50 The process of developing a novel drug is time genetic association studies, and phenotype healthy volunteers. Apart from determining the consuming and costly. To increase the screening are valuable tools in the discovery of drug’s maximum tolerated dose by increasing the chances of successfully completing a clinical novel targets. To validate the relevance of the treatment dose until dose-limiting toxicity is trial leading to the approval of a new drug, the identified target for a particular disease, studies reached (dose escalation), the drug’s most choice of appropriate preclinical models is of are performed to investigate whether target common and serious adverse effects (AEs) as utmost importance. Identifying a safe, potent, modulation is disease modifying. 2 Eventually, well as pharmacological, pharmacodynamic, and and efficacious drug requires thorough lead compounds are obtained and their potential pharmacokinetic properties are evaluated. 4 preclinical testing, which evaluates aspects of to interact with the target as well as their effect Approximately 70% of drug candidates move pharmacodynamics, pharmacokinetics, and on the biological system is evaluated. Thousands from Phase I to Phase II, in which therapeutic toxicology in in vitro and in vivo settings. of modifications and variations of these lead efficacy of the IND in patients is assessed. 5 Phase Nevertheless, merely a small fraction of compounds are synthesised and tested during II studies typically involve several hundred investigational new drugs tested in clinical preclinical activities. Once an optimised patients. The study population is well defined by trials after passing preclinical evaluation compound is identified, this investigational new inclusion and exclusion criteria, and based on the eventually lead to a marketed product. Hence, drug (IND) becomes a candidate for clinical dose or dose range determined in Phase I, dose there is a need for optimising current standard trials involving human subjects. response in patients and the preclinical approaches to better mimic the Clinical trials are conducted over different drug’s biological activity are complexity of human disease mechanisms. phases (Phase I-IV), starting from a small evaluated. Comparison of number of subjects and extending to large (i) pre- and

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Figure 1. From basic research to approved drug the therapeutic index of a drug, describing the Target identi cation ratio of the dose causing toxicity and the dose Basic research Target validation eliciting a therapeutic effect. Ideally, the therapeutic index is large to indicate a wide therapeutic window. 1 Lead identi cation 5,000-20,000 compounds Lead optimisation Pharmacokinetics – what does the body do to the drug? Pharmacodynamics The effect of a drug is determined by the amount Preclinical research Pharmacokinetics of active drug present in the body particularly at 250 compounds Toxicology the target site. This, in turn, depends on absorp - tion, distribution, metabolism, and excretion Phase I studies (ADME) of the compound. Pharmacokinetics Clinical studies Phase II studies describes changes in plasma concentrations over 5 compounds Phase III studies time as a consequence of ADME. ADME profiling is critical for establishing dose range and Regulatory approval administration schedule for subsequent phases Approved drug Drug launch of the . 1,8,9 1 compound Post-marketing/Phase IV studies Most drugs are administered orally and need to be absorbed in the gastrointestinal tract to post- treatment status of patients and (ii) cohort and provide the opportunity of detecting enter the bloodstream, allowing them to be response of patients receiving IND and a placebo unique AEs. In some cases, this might result in transported to their site of action. On its way to drug provide preliminary data on effectiveness. withdrawal of the drug from the market or the target site, the drug reaches the liver, where Although researchers obtain indications regarding restriction to particular uses. On the other hand, first-pass metabolism takes place. Consequently, the drug’s benefit, Phase II studies are not Phase IV studies may also open up new markets the drug concentration – and thus its bio- comprehensive enough to provide sufficient by demonstrating effectiveness for new availability – is reduced before entering systemic evidence. During Phase II, subjects are carefully indications. 6,7 circulation. Intravenous drug administration monitored for AEs to further assess safety of the bypasses the first-pass effect, resulting in greater drug. Moreover, these trials commonly determine Preclinical studies bioavailability. Once in the circulation, the the optimum dose regimen to be used in Preclinical studies aim at providing information drug is transported to different tissues. Phase III. 4,6 about safety and efficacy of a drug candidate Distribution of the compound throughout the About one-third of tested INDs transition before testing it in humans. Furthermore, they body is determined by (i) the drug’s affinity for into Phase III having 100-500 patients and with can provide evidence for the compound’s plasma proteins, (ii) the drug’s molecular the primary objective of confirming the biological effect and usually include both in vitro properties and polarity, and (iii) tissue therapeutic benefit of the IND as well as its safety and in vivo studies. Preclinical studies have to vascularisation. After entering the body, drugs and efficacy in the intended indication. 4 comply with the guidelines dictated by Good are metabolised to facilitate elimination. Moreover, the use of different dosages and study Laboratory Practice to ensure reliable results 5 Metabolism refers to the chemical alteration of populations and combination with other and are required by authorities such as the FDA the parental drug into pharmacologically active therapeutic agents are investigated to provide before filing for approval as IND. Insights into the or inert metabolites. To ensure adequate long- information regarding indications and contra - compound’s dosing and toxicity levels are term dosing and appropriate steady-state indications as well as dose range and AEs. As essential to determine whether it is justified and concentrations of the drug, it is critical to Phase III studies include a larger cohort and have reasonably safe to proceed with clinical studies obtain information on drug elimination from a longer duration than Phase I and II studies, they and are provided by studies on pharmacokinetics, the body (clearance). Clearance is mainly can potentially reveal rare and long-term side pharmacodynamics, and toxicology. 5 achieved via the renal and hepatic routes; effects. Based on the outcome, 25% to 30% of however, pulmonary clearance plays a major INDs progress to the next phase. 6,7 Pharmacodynamics – what does the drug do role for volatile drugs such as anaesthetics. 1 Phase IV studies are long-term and typically to the body? Concomitant disease, lifestyle factors, and conducted after regulatory agency approval Pharmacodynamics describes the relationship patient’s age can affect clearance and these are (post-marketing studies). 6 They often involve between the concentration of a drug in the body frequently studied in later stages of the clinical more than 10,000 individuals of the relevant and its biological effect (dose response). This trial. 8 When the rate of clearance equals the rate patient population and aim at gathering includes addressing the question, how potent and of absorption, a so-called steady state is additional information on safety, efficacy, and efficacious the drug is with regard to its desired reached. Typically, maintaining a stable steady new indications. Thus, Phase IV trials assess the pharmacological effect, including safety aspects state level is desirable and can be achieved drug’s real-world effectiveness in an extensive and AEs. Thus, pharmacodynamics establishes through repeated dosing. Eventually, the drug

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and its metabolites are excreted from the body pharmaceutical testing is the mouse. mainly through urine or faeces. The genomes of mouse and man are highly similar: 99% of all mouse genes overlap with Toxicology – it is potent, but is it safe? those of humans. Additionally, genomic To determine whether a drug is safe for testing in manipulation in this organism has become fairly human subjects, preclinical toxicology studies are simple. Nevertheless, species-specific differences performed to identify the treatment regimen in host immune response, drug metabolism, and associated with the least degree of toxicity and tumour heterogeneity affect therapeutic out - thus determine a suitable and safe starting dose comes. Differences in pharmacokinetics and for clinical trials. Additionally, they can be used pharmacodynamics among species are also not to establish biomarkers for monitoring potential negligible and thus, mouse models often suffer AEs later. Starting with single-dose studies to from poor predictive power regarding clinical identify organs that might be subject to drug efficacy. 11 However, lack of superior alternatives toxicity, preclinical in vivo studies continue with makes mouse models the gold standard for repeated-dose approaches. The treatment testing cancer-targeting drugs. regimen ideally mimics the intended clinical within the body where they partake in crosstalk Classically, such mouse cancer models were design with respect to treatment duration, and interaction with millions of other cells. limited to transplantation of cultured human schedule, and route of administration. Other Consequently, more sophisticated preclinical tumour cells (cell lines) to immunodeficient mice studies evaluate carcinogenicity, genotoxicity, models are required to establish the inves ti - such as nude or severe combined immuno - and reproductive toxicity. While the drug’s gational compound’s safety profile before deficiency (SCID) mice. 12 Transplantation of genotoxic effect is usually studied based on its transitioning to a clinical setting. cells, tissue, or organs from one species to potential to induce mutations in yeast-based in another is called xenografting. In these cell line- vitro systems, carcinogenicity and reproductive In vivo models – is the mouse the best derived xenograft (CDX) models, cancer cells are toxicity studies typically involve rats. As the experimental animal? injected subcutaneously and tumour growth tumorigenic effect of a drug may only become In vivo studies consider the complete organism curves are established by measuring the size of evident after prolonged exposure, carcinogenicity based on various animal models. Similar to the tumour in regular intervals. Treatment of studies comprise continuous drug administration studies in humans, animal testing is tightly tumour-bearing mice with a drug candidate for a minimum of six months. regulated in most countries and permission from provides information regarding its potential to local ethical review boards is required to ensure reduce tumour growth and thus its in vivo The ideal preclinical model that no unnecessary harm is done to the efficacy. However, these cell lines have been accurately mimics human experimental subjects. Recent advances have passaged under artificial conditions that do not disease refined the use of animal models in drug recapitulate the natural tumour micro environ - Obtaining relevant results from through non-invasive imaging ment. Consequently, CDX models may lack studies with a high degree of generalisability technologies, microsampling, and telemetric similarity with human disease. 11,13 To improve requires appropriate preclinical models that are monitoring. 10 Naturally, controlling experimental clinical relevance, a range of different mouse as comparable to the target population as settings is far more complicated for in vivo models has been developed and is used in in vivo possible. Typically, this involves a series of studies and, due to the complexity of the living experiments: experiments using in vitro, in vivo , and more organism, compounds may behave differently G Patient-derived xenograft (PDX) models: recently, also in silico models. from what is expected based on results obtained Tissue from a patient’s primary tumour is in a test tube. directly implanted into the animal. This In vitro models – studying the drug in a petri The choice of appropriate animal models strategy omits in vitro adaptation of tumour dish depends on myriad criteria and requires cells and, thus, these models are more similar In vitro studies are a relatively fast, simple, and understanding of species-specific physiology and to human disease in terms of stromal cost efficient way of preclinical testing. Those similarity with regard to the target organ, composition and tumour heterogeneity, in studies utilise cell, tissue, and organ cultures, or metabolic pathways as well as financial, contrast to classical CDX models. The PDX focus on particular cell components such as regulatory, and ethical considerations. Typically, approach is challenging; however, recent proteins or other biological macromolecules. in vivo studies are performed in a rodent (e.g, advances in sample retrieval and transplan - In vitro studies permit tight control and monitoring mouse, guinea pig, hamster) and non-rodent tation technology made this method feasible. of experimental settings and often provide model to comply with FDA requirements. Mice, To date, PDX models consist of almost mechanistic evidence for the investigational rats, and dogs are among the most frequently exclusively subcutaneous transplants. compound’s mode of action. While having the used animal models while testing in primates G Orthotopic tumour models: Tumours are potential to provide mechanistic insights, in vitro (e.g., monkeys, apes, etc.) is performed implanted into the organ of origin (i.e. models are constrained by the fact that isolated occasionally and typically for larger molecules. 9 orthotopically) to better mimic the micro - cells may not behave in a petri dish as they would One of the most popular animal models in environment and recapitulate metastasis

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pathways of human tumours. 11,13 Conse - evaluation are approved by the FDA. 11 The fact Elsevier Health Sciences; 2017. quently, orthotopic models are more that most anti-cancer drugs do not pass efficacy 8. Fitzpatrick S. The clinical trial protocol. clinically relevant. Orthotopic PDX models evaluation in Phase II and III studies suggests Buckinghamshire: Institute of Clinical are technically challenging and thus that currently used preclinical models fail at Research; 2005. uncommon, while orthotopic transplantation appropriately mimicking tumour heterogeneity, 9. Faqi AS, ed. A comprehensive guide to is widely used for CDX models. 11 host factors, and drug resistance mech - toxicology in preclinical drug development. G Genetically engineered mice (GEM): anisms. 15,16 Nevertheless, preclinical research is Waltham, MA: Elsevier; 2013. Genetic engineering has given rise to indispensable to protect human subjects in 10. Everitt JI. The future of preclinical animal humanised mouse models and provides clinical trials. Adequate design of preclinical models in pharmaceutical discovery and valuable tools for translational research. studies and careful choice of model systems are development: A need to bring in cerebro to Through genetic manipulation, mutations in vital to ensure relevant results that translate into the in vivo discussions. Toxicol Pathol. oncogenes or tumour suppressor genes applicability in clinical settings. 2015;43(1):70–7. associated with human malignancies are 11. Herter-Sprie GS, Kung AL, Wong KK. New introduced. In GEM, tumours develop Conflicts of Interest cast for a new era: Preclinical cancer drug orthotopically from initiation through The author declares no conflicts of interest. development revisited. J Clin Invest. progression in their native microenvironment 2013;123(9):3636–45. recapitulating human tumourigenesis. 11 References 12. Vandamme T. Use of rodents as models of Hence, preclinical studies in GEM have the 1. Ng R. Drugs: From discovery to approval. human diseases. J Pharm Bioallied Sci. potential to provide more relevant data for 3rd ed. New Jersey: Wiley-Blackwell; 2015. 2014;6(1):2. subsequent clinical trials. 2. Hughes JP, Rees S, Kalindjian SB, Philpott 13. Hoffman RM. Patient-derived orthotopic KL. Principles of early drug discovery. Br J xenografts: Better mimic of metastasis than In silico models – the computer’s role in drug Pharmacol. 2011;162(6):1239–49. subcutaneous xenografts. Nat Rev Cancer. development 3. European Medicines Agency. ICH Topic E 2015;15(8):451–2. Progress in bioinformatics over the past decades 8 General Considerations for Clinical 14. Amberg A. In silico methods. In: Vogel has made in silico studies attractive so that they Trials. 1998 [cited 2017 September 10]. HG, Maas J, Hock FJ, Mayer D, eds. Drug often precede or complement in vitro and in vivo Available from: http://www.emea.eu.int. Discovery and Evaluation: Safety and studies. In silico models are based on computer Published 1998. Pharmacokinetic Assays. Berlin, simulations and provide information on how an 4. Friedman LM, Furberg CD, Demets DL. Heidelberg: Springer; 2013:1273–96. investigational compound might behave in Fundamentals of clinical trials. 4th ed. 15. Day CP, Merlino G, Van Dyke T. Preclinical subsequent in vitro and in vivo experiments. 14 New York: Springer Science+Business mouse cancer models: A maze of Apart from technological requirements, these Media LLC; 2010. opportunities and challenges. Cell. computer simulations demand expert knowledge 5. U.S. Food & Drug Administration. 2015;163(1):39–53. in biochemistry and molecular biology. The Drug Development Process – Step 2: 16. Al-Lazikani B, Banerji U, Workman P. Preclinical Research. 2017. [cited 2017 Combinatorial drug therapy for cancer in Preclinical research is September 10]. Available from: the post-genomic era. Nat Biotechnol. indispensable https://www.fda.gov/forpatients/ 2012;30(7):679–92. Despite all efforts to identify relevant animal approvals/drugs/ucm405658.htm. models to ensure a significant translational value, 6. U.S. Food & Drug Administration. drugs often show different pharmacodynamic The Drug Development Process - Step 3: Author information characteristics when administered to human Clinical Research. 2017. [cited 2017 Jennifer Honek has a background in subjects. Thus, merely one out of five September 10]. Available from: molecular biotechnology and holds a PhD in investigational drugs tested in clinical trials https://www.fda.gov/ForPatients/ Medicine. She has been active as a freelance eventually gains approval for clinical use. Some Approvals/Drugs/ucm405622.htm. medical writer since 2015 and also works for studies even report that only nine percent of 7. Waller DG, Sampson T. Medical a medtech company as a clinical trial lead. compounds passing preclinical efficacy pharmacology and therapeutics E-Book.

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